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Kerledex is usually well tolerated in properly selected patients. Discontinuation of therapy due to adverse events in U.S. controlled clinical trials was necessary in about 4% of patients receiving betaxolol in combination with chlorthalidone. The most frequent reasons for discontinuation were fatigue (1.1%) and bradycardia (0.9%). The following reasons for discontinuation of therapy were reported in 0.4% (2 patients each) of the 465 patients receiving the combination in U.S. controlled studies: myalgia, depression, insomnia, lethargy, palpitation, and elevated serum transaminase levels.

In controlled clinical trials, Kerledex has been evaluated versus placebo and/or its component monotherapies in doses of 5/12.5 mg, 5/25 mg, 10/12.5 mg, 10/25 mg, and 20/25 mg for treatment periods lasting 3 to 24 weeks. In these controlled studies, the most common adverse reactions to Kerledex were bradycardia, headache, dizziness, arthralgia, dyspepsia, and fatigue.

Kerledex adverse events with a 2% or greater frequency, and selected events with lower frequency, in these controlled studies are:

  Kerledex (n=465) 5/12.5–20/25 mg q.d. Placebo (n=199) Betaxolol (n=306) 5–20 mg q.d. Chlorthalidone (n=494) 12.5–25 mg q .d.
Body System/
Adverse Reaction
(%) (%) (%) (%)
Cardiovascular
  Bradycardia (heart rate < 50 BPM) 7.3 0 5.2 0.6
  Edema 0.9 0.5 1.0 0.8
Central Nervous System
  Headache 4.5 8.0 5.2 4.9
  Dizziness 3.9 3.5 4.6 4.9
  Fatigue 3.4 2.5 3.9 5.1
  Lethargy 1.9 0.5 3.3 2.4
Psychiatric
  Insomnia 0.6 0.5 1.0 1.6
  Nervousness 0.4 1.0 0.7 1.2
  Depression 0.4 0 0.7 0.2
Autonomic
  Impotence* 1.4 0.8 2.1 0.3
Metabolic
  Hypokalemia (serum K+<3.0 mEq/L) 2.4 0 0 5.1
Respiratory
  Dyspnea 1.1 0.5 1.3 0.4
  Pharyngitis 0.6 0 2.0 0.8
  Rhinitis  1.9 0 1.3 0.8
  Upper respiratory infection 4.5 6.5 4.9 6.1
Gastrointestinal
  Dyspepsia 3.7 1.0 2.6 3.0
  Nausea 1.1 1.0 1.3 0.8
  Diarrhea 1.1 1.0 2.3 1.6
Musculoskeletal
  Arthralgia 3.7 1.5 2.6 5.1
Skin
  Rash 1.3 1.0 0.7 0.8
*Percentage based on number of males: Kerledex n=282; placebo n=131; betaxolol n=188; chlorthalidone n=311.

The following selected (potentially important) adverse events have been reported in patients receiving Kerledex at an incidence of less than 2.0% in U.S. controlled and long-term clinical studies. It is not known whether a causal relationship exists between Kerledex and these events, they are listed to alert the physician to a possible relationship.

Autonomic: flushing, sweating.

Body as a whole: allergy, chest pain, fever, malaise, pain.

Cardiovascular: angina pectoris, hypotension, palpitations, syncope.

Central and peripheral nervous system: asthenia, ataxia, dysphonia, migraine, neuralgia, numbness, paresthesia, twitching, vertigo.

Endocrine: sialadenitis.

Gastrointestinal: anorexia, constipation, dry mouth, dysphagia, gastroenteritis, increased appetite, mouth ulceration, rectal disorder, stomatitis, vomiting.

Hearing and vestibular: earache, tinnitus.

Hematologic: anemia, hyperhemoglobinemia, leucocytosis, lymphadenopathy.

Liver and biliary: cholecystitis, increased AST, increased ALT.

Metabolic and nutritional: diabetes mellitus, hypercalcemia, hyperglycemia, hyperlipemia, hyperuricemia, increased alkaline phosphatase, weight gain, weight loss.

Musculoskeletal: arthropathy, myalgia, neck pain, tendinitis.

Platelet, bleeding and clotting: purpura.

Psychiatric: amnesia, emotional lability, euphoria, decreased libido, hallucinations, hysteria, nightmares.

Reproductive: amenorrhea, dysmenorrhea, dyspareunia, epididymitis, menstrual disorder, ovarian disorder, prostatitis.

Respiratory: apnea, bronchitis, bronchospasm, cough, epistaxis, sinusitis.

Skin: follicular rash, photosensitivity, pruritus, skin disorders.

Special senses: dysgeusia.

Urinary: cystitis, dysuria, micturition disorder, polyuria, renal calculus, urethral disorder.

Vascular: cerebrovascular disorder, cold extremities (peripheral ischemia), leg cramps, phlebitis.

Vision: abnormal lacrimation, abnormal vision, conjunctivitis.

Other adverse events that have been reported with the individual components are listed by body system below:

Betaxolol: Autonomic: salivation;

Body as a whole: rigors;

Cardiovascular: arrhythmia, atrioventricular block, heart failure, hypertension, myocardial infarction, thrombosis;

Central and peripheral nervous system: neuropathy, speech disorder, stupor, tremor;

Hearing and vestibular: deafness, labyrinth disorders;

Hematologic: thrombocytopenia;

Metabolic and nutritional: acidosis, hypercholesterolemia, hyperkalemia, increased LDH, thirst;

Musculoskeletal: muscle cramps;

Psychiatric: abnormal thinking, impaired concentration, confusion;

Reproductive: breast pain, breast fibroadenosis, Peyronie's disease;

Respiratory: flu, pneumonia;

Special senses: taste loss;

Skin: alopecia, eczema, erythematous rash, hypertrichosis;

Urinary: oliguria, proteinuria, abnormal renal function, renal pain;

Vascular: intermittent claudication, thrombophlebitis;

Vision: blepharitis, cataract, dry eyes, iritis, ocular hemorrhage, scotoma.

Potential adverse effects

Although not reported in clinical studies with betaxolol, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and may be considered potential adverse effects of betaxolol: Central nervous system: Reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability with slightly clouded sensorium, and decreased performance on neuropsychometric tests; Allergic: Fever combined with aching and sore throat, laryngospasm, respiratory distress; Hematologic: Agranulocytosis, thrombocytopenic purpura, and non-thrombocytopenic purpura; Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis; Vascular: Raynaud's phenomena.

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with betaxolol during investigational use and extensive foreign experience. Dry eyes and skin rash, however, have been reported. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. Patients should be closely monitored following cessation of therapy.

Chlorthalidone

Cardiovascular: orthostatic hypotension; Central and peripheral nervous system: xanthopsia; Gastrointestinal: cramping, gastric irritation, jaundice (intrahepatic cholestatic jaundice), pancreatitis; Hematologic: agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia; Dermatologic-Hypersensitivity: urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell's syndrome (toxic epidermal necrolysis); Miscellaneous: glycosuria, muscle spasm, restlessness, weakness.